The present invention relates to the field of antimicrobial (antiseptic or microbicidal) formulations for medical and other purposes, the formulations being in particular aqueous solutions which contain an active substance with antimicrobial and antiendotoxic activity as explained by an irreversible N-methylol group transfer to the microbial cell wall and endotoxins.
Substantially the compound taurolidin may be mentioned as the active substance whose activity is interpreted in terms of said methylol group transfer. Taurolidin is a substance which can be structurally derived from the aminosulfonic acid taurine. Taurolidin has the structural formula (I) and, in aqueous solution, is in equilibrium with taurultam (II) and methylol taurultam (III).

The preparation of taurolidin was first described in the Swiss patent application CH 482713 A. Taurolidin is prepared by reacting taurinamide(2-aminoethanesulfonamide) with 1.5 equivalents of formaldehyde or its hydration product methylene glycol CH2(OH)2 formed in aqueous solution. The known process was considerably improved by an improved process for the preparation of taurinamide according to EP 0 863 133 B1.
The formation of taurolidin from taurinamide and formaldehyde can be described as a condensation process in which 2 equivalents of taurinamide and 3 equivalents of formaldehyde participate, which gives a ratio of taurinamide to formaldehyde of 1:1.5 for the overall compound taurolidin. The hydrolytic cleavage of taurolidin according to the above equation results in the formation of the compounds methylol taurultam and taurultam, which, considered individually, may be regarded as condensates of taurinamide with 2 equivalents or 1 equivalent, respectively, of formaldehyde.
Taurolidin has long been commercially available in the form of aqueous solutions under the trade name Taurolin®, in particular as Taurolin 2% instillation solution having a content of 2.0 g of taurolidin and 5.0 g of polyvinylpyrrolidone per 100 ml of water, and as Taurolin® Ringer 0.5% surgical irrigation solution with 0.50 g taurolidin, 1.25 g of polyvinylpyrrolidone and a mixture of inorganic salts per 100 ml of water.
The medical uses of Taurolin® solutions are based substantially on the antimicrobial and antiendotoxic activity of taurolidin. The 0.5% Taurolin solution serves in particular for the intraoperative irrigation of the abdominal cavity, while applications by instillation via drains are stated for 2% Taurolin solutions in particular in diffuse purulent peritonitis and perforative appendicitis. Other applications stated by the manufacturer are prophylaxis in the case of soft tissue and bone injuries and for thoracic empyema. In various patent applications and scientific publications, further potential uses of Taurolin®, for example in dental medicine and oral hygiene, in tumor diseases and in dermatology, are described, and the effect on a large number of physiological parameters by local or parenteral administration of Taurolin® solutions or taurolidin solutions was investigated.
It has furthermore already been known since 1989 that the known Taurolin® solutions can also be used for controlling so-called “catheter sepsis” (cf. Mughal, Br. J. Sur. (1989) 76(1), pages 15 to 21; cf. also J. of the Critically Ill (1990) 6(6), pages 228 to 231). “Catheter sepsis” is one of the terms for severe complications which may occur in persons in whom catheters are implanted for repeated supply of medicaments or nutrient solutions or for hemodialysis purposes. As “catheters” may also be regarded the so-called port systems which are likewise permanently implanted and provide external access to central blood vessels of a patient. If, during the use of the permanently applied catheters or port systems, these catheters or port systems become populated with pathogenic bacteria, for example through a formation of biofilms on the inner walls of the catheters or port systems or the associated pathways, such as, for example, hollow needles, the patient may suffer dangerous local and in particular systemic infections (sepsis).
It has therefore long been known in principle to fill catheters and port systems with antimicrobial solutions which prevent colonization of the catheters and port systems by microorganisms and the formation of biofilms controllable only with difficulty with antibiotics or antiseptic agents, during those periods when, for example, no medicaments or nutrient solutions are supplied or no blood is taken.
European Patent application EP 0 946 221 A1 describes the use of a Taurolin® solution as a lock solution, it being intended that the lock solution be washed into the blood stream before resumption of operation of the catheter with a salt solution. Since the lock solution enters the patient's body in such a procedure, the lock solution must fulfill all preconditions which are set for medicaments to be administered parenterally.
While EP 0 946 221 A1 substantially describes the use of the customary 2% by weight Taurolin® solutions which contain polyvinylpyrrolidone in addition to taurolidin, European Patent EP 1 089 738 B1 discloses a use of taurolidin for lock solutions in modified form, in particular as a solution of taurolidin in a buffer system comprising trisodium citrate and citric acid. The buffer system serves for optimizing the solubility of the taurolidin and its antibacterial activity, in addition the anticoagulation properties of citrate being utilized for preventing blocking of the catheter exits by clots which can be formed from blood. Lock solutions of the type described in EP 1 089 738 B1 are today as a rule no longer washed into the circulation but sucked out of the catheter or port system before it is put into operation again. This has, inter alia, the advantage that the lock solutions do not enter the patient's body and are therefore not regarded as therapeutic agents, which have to meet strict registration requirements for therapeutic agents but as disinfectants or antiseptic agents acting only externally.
Although, for example in comparison with solutions of antibiotics, the use of taurolidin in lock solutions, in particular in lock solutions with added citrate, leads to a decisive improvement with regard to the control of infections which are caused by microbial contamination of catheters and port systems, improvements are still possible in said area. Although taurolidin solutions are effective against an extremely broad spectrum of bacteria (prokaryotic microorganisms), its efficacy against eukaryotic microorganisms (fungi; e.g. yeasts or molds) is limited.
Owing to the limited solubility of taurolidin in aqueous media, the activity of taurolidin-based aqueous antimicrobial solution cannot be arbitrarily increased by concentration increases. This observation relates not only to lock solutions but generally to taurolidin-based microbicidal (antimicrobial; antiseptic) aqueous solutions, also for other known or conceivable intended uses.